Tangle pathology is one of the major pathological hallmarks of Alzheimer's disease (AD) and related tauopathies, where microtubule associated protein - tau (or tau) acquires a pathological protein conformation, accumulates as neurofibrillary tangles (NFTs) and coincides with neurodegeneration. Increasing evidence suggests that age-related alterations in inflammatory processes also closely associated with NFT pathology in the brains of individuals with human and mouse models of tauopathies. While it is hypothesized that accumulation misfolded proteins released from injured neurons and synapses may trigger neuroinflammation, it is not clear how misfolding of proteins intrinsic to neurons, such NFTs, trigger neuroinflammation. Previous studies have documented that neurodegenerative lesions caused by truncation of human tau promoted inflammatory response including upregulation of numerous immune molecules and morphological activation of microglial cells in a rat model of tauopathy. Furthermore, NFT lesions in this model also promoted infiltration and recruitment of peripheral leukocytes into the brain parenchyma. In another study, microglial activation preceded NFT pathology in P301S mouse model of tauopathy. We have recently demonstrated a progressive and age-dependent neuroinflammation in hTau mouse model of tauopathy. First, robust microglial activation was observed in 12 month and 18 month old hTau mice compared to 18 month old non-transgenic controls. Second, a significant increase in mRNA levels for inflammatory molecules such as nitric-oxide synthase-2 (NOS2) and monocyte chomoattractant protein (MCP1 or CCL2) was observed in the brains of much younger, 6 month old hTau mice. Finally, enhancing microglia-specific neuroinflammation accelerated tau phsphorylation, aggregation and behavioral impairment in hTau mouse model of tauopathy. Notably, the interleukin-1 (IL-1) released by reactive microglia induces tau phosphorylation via activating neuronal IL-1 receptor (IL-1R) and p38 mitogen activated protein kinase pathway. While these studies suggested that microglial activation and IL-1 signaling is involved in accelerating tau pathology and neurodegeneration, the factor(s) driving microglial activation and/or secretion of IL-1 is unclear. In our preliminary studies, we have observed that misfolded tau could act as 'danger signal' to stimulate secretion of IL-1? via assembly of a multiprotein complex called inflammasome, which includes ASC as a key component of inflammasome complex. Based on this novel phenomenon from our preliminary studies, we propose to determine whether misfolded tau trigger inflammasome assembly/maturation of IL-1? and lead to microglial activation in vitro (Specific Aims 1) and in rTg4510 regulatable mouse model of tauopathy (Specific Aim 2). We also propose to determine whether blocking inflammasome assembly via genetic deficiency of ASC prevents IL-1? activation, microglial neuroinflammation and block tau pathology in hTau mice crossed to ASC-/- and ASCfl/fl mice (Specific Aim 3). The outcome of these studies will provide greater understanding of the tau pathology and innate immune responses mediated by inflammasome/IL-1? and present opportunities in identifying novel therapeutic targets against tauopathies.